The history of Intrauterine Devices (IUDs) dates back to the early 1900s. The first IUD was developed by the German physician, Dr. Richter of Waldenburg. His device was made of silkworm gut and was not widely used1. 1 Thiery, Michel (March 1997). “Pioneers of the intrauterine device”. European Journal of Contraception and Reproductive Health Care 2 (1): 15-23.
Dr. Ernst Gräfenberg, another German physician created the first Ring IUD, Gräfenberg's ring, made of silver filaments.
Dr. Jack Lippes helped begin the increase of IUD use in the United States in the late 1950s. In this time, thermoplastics, which can bend for insertion and retain their original shape, became the material used for first-generation IUDs. Lippes also devised the addition of the monofilament nylon string, which facilitates IUD removal. His trapezoid shape Lippes Loop IUD became one of the most popular first generation IUDs.
In the following years, many different shaped plastic IUDs were invented and marketed including Dalkon Shield, whose design caused bacterial infection and led to thousands of lawsuits. Although the Dalkon shield was removed from the market, it had a lasting, negative impact on IUD use in the United States2. 2Thiery M (June 2000), “Intrauterine contraception: from silver ring to intrauterine contraceptive implant”, Eur. J. Obstet. Gynecol. Reprod. Biol. 90 (2): 145-52
The invention of the copper IUD in the 1960s brought with it the capital T-shaped design used by most modern IUDs. U.S. physician, Dr. Howard Tatum determined that the T-shape would work better with the shape of the uterus, which forms a T when contracted. He predicted this would reduce rates of IUD expulsion1.
Together, Tatum and Chilean physician Jaime Zipper discovered that copper could be an effective spermicide and developed the first copper IUD, TCu200. Improvements by Dr. Tatum led to the creation of the TCu380A (ParaGard), which is currently the preferred copper IUD1.
The hormonal IUD (respectively Intrauterine Systems, IUS) was also invented in the 1960s and 1970s; initially the goal was to mitigate the increased menstrual bleeding associated with copper and inert IUDs. The first model, Progestasert, was conceived of by Dr. Antonio Scommengna and created by Dr. Tapani J. V. Luukkainen, but the device only lasted for one year of use2. Progestasert was manufactured until 20013. 2Thiery M (June 2000), “Intrauterine contraception: from silver ring to intrauterine contraceptive implant”, Eur. J. Obstet. Gynecol. Reprod. Biol. 90 (2): 145-523Smith (pseudonym), Sydney (Mar. 8, 2003). “Contraceptive Concerns”. medpundit: Commentary on medical news by a practicing physician. Retrieved 2014-01-16
Three commercial hormonal IUSs are currently available on the market which are: Mirena®, which was also developed by Dr. Luukkainen and released in 1976, Jaydess® which is on the market since 2013 and Levosert® which is marketed in Belgium in the indication Heavy Menstrual Bleeding since 2014.
All market products is in common that the active compound released from the capsule is Levonorgestrel and that the frame on which the capsule is mounted is T-shaped.
In terms of safety and contraceptive efficacy today's intrauterine systems have reached a very high standard.
Although the use of modern IUSs can be considered basically as safe and efficient in rare cases the following side effects are reported:                abdominal pain,        infection,        irregular bleeding,        hormonal side effects,        uterine perforation (usually during the insertion procedure),        cervical laceration,        septic abortion,        ectopic pregnancy,        in some rare cases breaking of the frame,        pain and difficulties in insertion and/or in removal of the device and        expulsion of the IUS.        
The current invention relates essentially to the last three of the a.m. side effects, which correlate to the mechanical properties of the frame, namely to an improvement of the expulsion rate, avoidance of frame breaking, a better wearing comfort and easier (less painful) removal procedure.
Expulsion rates (besides irregular bleeding in the initial phase of the wearing period, infection and uterine perforation during insertion) is the most common side effect. In the literature a range from 2.2% to 11.4% of users from the first year to the 10th year are reported4. 4Kaneshiro B, Aeby T (2010). “Long-term safety, efficacy, and patient acceptability of the intrauterine Copper T-380A contraceptive device”. International Journal of Women's Health 2: 211-220
To improve the expulsion rate various approaches have been followed. Most of them relate to dimensions and design of the frame. Thus many approaches try to overcome the problem of expulsion by varying the shape of the frame. A large number of systems which contain essentially a continuous ring shaped frame are described in the literature. For example U.S. Pat. No. 3,431,906 discloses a diamond shaped frame, U.S. Pat. No. 3,516,403 discloses an isosceles triangle form.
Various rings shaped frames are also disclosed in U.S. Pat. No. 4,200,091 and in Bayer Schering Oy's International Patent Application WO2009/122016 which discloses an intrauterine delivery system with a closed continuous frame of a polygonal shape, wherein the drug containing reservoir is connected to the inner surface of the frame.
Even a ball shape frames have been proposed to improve expulsion rate. Thus WO 2010/082197 disclose a Copper based IUD, whereby the frame is made of a memory shape Nickel-Titanium alloy (NiTiNol®) wire, which returns into its original ball shape if released from the inserter tube.
U.S. Pat. No. 4,721,105 (Wildermesch) proposes to anchor the IUS with a thread in the uterus muscle to avoid expulsion in women, in particular in the immediate post-partum period.
Other approaches propose to reinforce and/or to give additional flexibility and/or strength/to the frame by integrating a supporting means into the frame. For example Bayer Schering Oy patent application WO2009/122016 proposed to add supporting means to the frame in a form of a core, fibre or wire. These supporting means can be made of any material which is inert and biologically compatible as long as it possesses sufficient strength and elasticity and remains unchanged for a sufficient period of time in the conditions prevailing in the uterus.
In addition to dimensions and design characteristics, frame material properties are important for an ideal intrauterine system. If no supporting means should be integrated into the frame, it is important that the polymer material as such shows already the required properties. Here besides breaking forces (tensile strength), and memory (ability of the T-frame to return to its original form after release from the insertion tube), flexibility/stiffness of the frame are further key parameters.
Flexibility/stiffness of the frame is particularly important for enhancing wearing comfort or reducing pain during removal of the intrauterine system. In combination with the frame design, memory effect and flexibility can be of relevance also with regard to expulsion.
Unfortunately to a certain extend the a.m. parameters behave in opposite directions, in other words materials with a high stiffness are not flexible enough and materials with a high flexibility do not show the required stiffness.
It is furthermore of importance that the material maintains its mechanical properties in vivo over the wearing period of up to 5 years. Thus a number of materials lose their stiffness at body conditions due to higher temperature (37° C.) and swelling in a humid environment (softening effect in the body/uterus). Also the breaking force of the material can vary over the wearing time due to oxidative or hydrolytic degradation. In the context of the current invention materials' biostability has been tested according to ISO 10993 Part 13 test method.
Last but not least for an in-vivo application biocompatibility has to be considered as a further important factor. Although many polymers are well tolerated and show a high stability in-vivo, e.g. some Polyurethanes have shown a genotoxic effect in animal tests.
Thus selection of a suitable material is by far an easy task. In principle a large number of frame materials had been described in the literature, for example in the International Patent application WO2004/26196 i.a. polyethylene, polypropylene, polymethylpentene ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, polycarbonate, polytetrafluoroethylene (PTFE), fluoroethylenepropylene (PEP), polyvinylidene fluoride (PVDF), polyvinylacetate, polystyrene, polyamides, polyurethane, polybutadiene, polyisoprene, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymers with vinyl acetate, poly(methacrylate), polymethyl (meth)acrylate, poly(vinylidene) chloride, poly(vinylidene) ethylene, poly(vinylidene) propylene, polyethylene terephthalate, ethylene vinylacetate, a polyhydroxy alkoanate poly(lacticacid), poly(glycolic acid), poly(alkyl 2-cyanoacrylates), polyanhydrides, polyorthoesters, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer; ethylene/vinyloxy-ethanol copolymer, hydrophilic polymers such as the hydrophilic hydrogels of esters of acrylic and methacrylic acids, modified collagen, cross-linked polyvinyl alcohol, cross-linked, partially hydrolyzed polyvinyl acetate, silicone elastomers, especially the medical grade polydimethyl siloxanes, polyvinylmethylsiloxanes, other organopolysiloxanes, polysiloxane, neoprene rubber, butyl rubber, epichlorohydrin rubbers, hydroxyl-terminated organopolysiloxanes of the room temperature vulcanizing type which harden to elastomers at room temperature following the addition of cross-linking agents in the presence of curing catalysts, two-component dimethylpolysiloxane compositions which are platinum catalysed at room temperature or under elevated temperatures and capable of addition crosslinking as well as mixtures thereof had been disclosed as suitable frame materials.
WO 2011/039418 (Bayer Schering Pharma Oy) discloses ring shaped frames made of thermoplastic polyurethane elastomer. A large number of polyurethane based polymers are disclosed in this application. These polymers are obtainable from a polycarbonate polyol or a mixture of a polycarbonate polyol and a polyether and/or polyester polyol, 1,6-hexamethylene diisocyanate and optionally additional (cyclo)aliphatic diisocyanates and at least one difunctional chain extender. As chain extenders a mixture of a straight chain oligomer, prepared from 1,6-hexanediol and ε-caprolactone, and hydroquinone bis(2-hydroxyethyl)-ethers are disclosed. Preferred chain extenders are long chain aliphatic diol, such as 1,10-decanediol or 1,12-dodecanediol.
It has to be noted that not only the selection of the chain extender influences the material properties but in particular the amount/ratio of the different compounds used for the preparation of the TPU polymer. Thus it has been surprisingly found that the ratio of the different compounds is a key element to achieve a material with does not change its material properties when used in-vivo.
The wide range of polymers disclosed in the a.m. application (WO 2011/039418) are suitable for ring shaped frames. However, as described below in more detail, only a small selection of these polymers is suitable for T-frames. Thus in general ring shaped frames show a higher stiffness due to their closed structure compared to the open form structure in T-frames. Therefore, stiffness is less critical in ring shaped frames.
In addition to the a.m. polymers also biodegradable polymers have been proposed in the literature, e.g. in EP 0873751 (Takeda Chemical Industries). This patent application discloses a biodegradable IUD, wherein an active agent is dispersed in a biodegradable polymer which is mould to a predetermined shape of a ring. Said IUD does not comprise separate frame and reservoir structures.
However, biodegradable polymers can be used only for contemporary supporting means and are therefore rather used for therapeutic indications than for contraception.
Also metal based frames are known, e.g. as described in the a.m. International Application WO 2010/082197, which discloses a memory shape Nickel-Titanium alloy wire as frame material.
Currently the most common T-frame material is polyethylene (PE) as is offers a good compromise between all relevant parameters (flexibility; stiffness; memory effect/rebound; breaking force) and essentially maintains the properties in an in-vivo environment (humidity and at body temperature) over the whole wearing period. Thus it is of no surprise that the current market products Mirena® and Jaydess® use polyethylene based frames. Usually Barium-Sulfate is added to the polymer to enhance X-ray visibility.
However, as the known and used materials (incl. PE) have their strength and weaknesses, the search for an optimal polymer is an ongoing and unsolved problem.
The a.m. Bayer Schering Pharma Oy patent application WO2011/039418(A1) discloses intrauterine systems comprising a flexible, elastic continuous frame comprising a thermoplastic polyurethane elastomer (TPU) and a reservoir with the active substance connected to the frame. The disclosed TPU elastomers show similar properties as the commonly used Polyethylene (PE) but are twice more flexible (soft) than PE. In particular they show a much higher tensile strength (less breaks in use) as it could be proven in various comparison tests.
Also with respect to the influence of temperature and humidity TPU is advantageous as it could be shown in our comparison (see FIG. 3/8). In this experiment material behaviour at body conditions +37° C./wet was mimiced by immersing the samples into Ringer physiological solution for 7 and 21 days and then immediately determining elastic modulus by DMA (Dynamic-Mechanical-Analysis).
Useful thermoplastic polyurethanes and thermoplastic polyurethane elastomers are also disclosed in WO 2009/122016 (Bayer Schering Pharma Oy application). Such materials are commercially available and include polyurethane copolymers, such as block and random copolymers that are polyether based, polyester based, polycarbonate based, aliphatic based, aromatic based and mixtures thereof. Examples of such polymers are known under the trade names Carbothane®, Tecoflex®, Tecothane®, Tecophilic®, Tecoplast®, Pellethane®, Chronothane® and Chronoflex®.
In conclusion TPU's appear to be a good alternative for PE. However, as mentioned above, only a selection of the wide variety of the TPU materials known in the literature can be used for the manufacture of T-frames. Thus the majority of the TPU's disclosed in WO2011/039418 A1 unfortunately change their mechanical properties under in-vivo conditions; in particular the temperature effect on stiffness is significant. Thus a softening occurs in vivo at temperatures around 37° C. and in the wet environment of the uterus.
This is less critical for frames as disclosed and claimed in the above mentioned International Patent application, as these frames have a continuous closed ring shape, which show a certain stability respectively stiffness due to their closed design. However, for an open T-frame design the known thermoplastic polyurethanes are less suitable, as the material stiffness is not sufficient at body temperature.